ClinVar Miner

Submissions for variant NM_006941.4(SOX10):c.482G>A (p.Arg161His)

gnomAD frequency: 0.00001  dbSNP: rs750566714
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill RCV001095698 SCV001251510 uncertain significance Waardenburg syndrome type 2E criteria provided, single submitter research This SOX10 c.482G>A (p.R161H) variant has been reported previously in one individual with Waardenburg syndrome 2 (PMID: 21898658).
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital RCV001095698 SCV001478233 pathogenic Waardenburg syndrome type 2E 2019-01-01 criteria provided, single submitter clinical testing
GeneDx RCV001555269 SCV001776654 likely pathogenic not provided 2023-08-27 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21898658, 31152317, 32853555, 36672963, 34142234, 33865100, 33442024, 33597575)
Invitae RCV001555269 SCV003444389 uncertain significance not provided 2022-07-03 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg161 amino acid residue in SOX10. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25077900, 27562378, 32908489). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SOX10 function (PMID: 21898658). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 873468). This missense change has been observed in individual(s) with Waardenburg syndrome (PMID: 21898658). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 161 of the SOX10 protein (p.Arg161His).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001095698 SCV003845146 likely pathogenic Waardenburg syndrome type 2E 2023-02-23 criteria provided, single submitter clinical testing Variant summary: SOX10 c.482G>A (p.Arg161His) results in a non-conservative amino acid change located in the High mobility group box domain (IPR009071) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 237008 control chromosomes (gnomAD). c.482G>A has been reported in the literature in one individual affected with Waardenburg syndrome 2 (Chaoui_2011) and individuals affected with hearing loss (Zazo Seco_2016, Roman_2020, Wang_2021), including one de novo occurrence (Zazo Seco_2016). These data indicate that the variant is likely to be associated with disease. At least one functional study reports this variant results in activating the Cx32 promoter in a manner similar to that of the wild-type protein, but reducing its activity on MITF prmoter and RET enchancer and partially protein redistributed in the cytoplasm. Three ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance, likely pathogenic and pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV001095698 SCV004244346 likely pathogenic Waardenburg syndrome type 2E 2024-01-03 criteria provided, single submitter clinical testing Criteria applied: PM1,PM2,PM5,PP3,PS2,PS4

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